Development of chemokine network inhibitors using combinatorial saturation mutagenesis
Abstract Targeting chemokine-driven inflammation has been elusive due to redundant pathways constituting chemokine-immune cell networks. Tick evasins overcome redundant pathways by broadly targeting either CC or CXC-chemokine classes. Recently identified evasin-derived peptides inhibiting both chemo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07778-6 |
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| author | Jhanna Kryukova Serena Vales Megan Payne Gintare Smagurauskaite Soumyanetra Chandra Charlie J. Clark Graham Davies Shoumo Bhattacharya |
| author_facet | Jhanna Kryukova Serena Vales Megan Payne Gintare Smagurauskaite Soumyanetra Chandra Charlie J. Clark Graham Davies Shoumo Bhattacharya |
| author_sort | Jhanna Kryukova |
| collection | DOAJ |
| description | Abstract Targeting chemokine-driven inflammation has been elusive due to redundant pathways constituting chemokine-immune cell networks. Tick evasins overcome redundant pathways by broadly targeting either CC or CXC-chemokine classes. Recently identified evasin-derived peptides inhibiting both chemokine classes provide a starting point for developing agents with enhanced potency and breadth of action. Structure-guided and affinity maturation approaches to achieve this are unsuitable when multiple targets are concerned. Here we develop a combinatorial saturation mutagenesis optimisation strategy (CoSMOS). This identifies a combinatorially mutated evasin-derived peptide with significantly enhanced pIC50 against three different inflammatory disease chemokine pools. Using AlphaFold 3 to model peptide - chemokine interactions, we show that the combinatorially mutated peptide has increased total and hydrophobic inter-chain bonding via tryptophan residues and is predicted to sterically hinder chemokine interactions required for immune cell migration. We suggest that CoSMOS-generated promiscuous binding activities could target disease networks where structurally related proteins drive redundant signalling pathways. |
| format | Article |
| id | doaj-art-021fcffaf3a14a3a8bdce717c846b88c |
| institution | OA Journals |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-021fcffaf3a14a3a8bdce717c846b88c2025-08-20T02:25:41ZengNature PortfolioCommunications Biology2399-36422025-04-018111710.1038/s42003-025-07778-6Development of chemokine network inhibitors using combinatorial saturation mutagenesisJhanna Kryukova0Serena Vales1Megan Payne2Gintare Smagurauskaite3Soumyanetra Chandra4Charlie J. Clark5Graham Davies6Shoumo Bhattacharya7Centre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveCentre for Human Genetics and RDM Cardiovascular Medicine, University of Oxford, Roosevelt DriveAbstract Targeting chemokine-driven inflammation has been elusive due to redundant pathways constituting chemokine-immune cell networks. Tick evasins overcome redundant pathways by broadly targeting either CC or CXC-chemokine classes. Recently identified evasin-derived peptides inhibiting both chemokine classes provide a starting point for developing agents with enhanced potency and breadth of action. Structure-guided and affinity maturation approaches to achieve this are unsuitable when multiple targets are concerned. Here we develop a combinatorial saturation mutagenesis optimisation strategy (CoSMOS). This identifies a combinatorially mutated evasin-derived peptide with significantly enhanced pIC50 against three different inflammatory disease chemokine pools. Using AlphaFold 3 to model peptide - chemokine interactions, we show that the combinatorially mutated peptide has increased total and hydrophobic inter-chain bonding via tryptophan residues and is predicted to sterically hinder chemokine interactions required for immune cell migration. We suggest that CoSMOS-generated promiscuous binding activities could target disease networks where structurally related proteins drive redundant signalling pathways.https://doi.org/10.1038/s42003-025-07778-6 |
| spellingShingle | Jhanna Kryukova Serena Vales Megan Payne Gintare Smagurauskaite Soumyanetra Chandra Charlie J. Clark Graham Davies Shoumo Bhattacharya Development of chemokine network inhibitors using combinatorial saturation mutagenesis Communications Biology |
| title | Development of chemokine network inhibitors using combinatorial saturation mutagenesis |
| title_full | Development of chemokine network inhibitors using combinatorial saturation mutagenesis |
| title_fullStr | Development of chemokine network inhibitors using combinatorial saturation mutagenesis |
| title_full_unstemmed | Development of chemokine network inhibitors using combinatorial saturation mutagenesis |
| title_short | Development of chemokine network inhibitors using combinatorial saturation mutagenesis |
| title_sort | development of chemokine network inhibitors using combinatorial saturation mutagenesis |
| url | https://doi.org/10.1038/s42003-025-07778-6 |
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